Structural Dynamics and Susceptibility of Anti-Alzheimer’s Drugs Donepezil and Galantamine against Human Acetylcholinesterase
DOI:
https://doi.org/10.48048/tis.2022.4587Keywords:
Binding free energy, Donepezil, Galantamine, Human acetylcholinesterase, Molecular dynamics simulationsAbstract
Alzheimer’s disease (AD) is a major public health problem worldwide due to an increase in the elderly population. The current pharmacotherapy for the early stages of AD is mainly dependent on cholinesterase inhibitors. Two of the most commonly used anti-AD drugs, donepezil (DPZ) and galantamine (GLM), are selective inhibitors for human acetylcholinesterase (hAChE). However, the inhibitory activity of DPZ on hAChE was more potent than GLM by ~85 times. To better understand the molecular basis for differences in mode of inhibition of hAChE by both drugs, molecular dynamics (MD) simulation was performed. The results showed that the active site residues of hAChE/DPZ had the higher hydrogen bond occupancies as compared to hAChE/GLM. Nevertheless, the 2 drugs directly formed hydrogen bonds with the catalytic residue H447 of hAChE. The per-residue free energy decomposition suggested that DPZ interacted with the residues in peripheral anionic site of hAChE, resulting in the greater binding affinity of DPZ than that of GLM toward hAChE. The binding free energy calculation based on MM-PBSA and MM-GBSA methods indicated that van der Waal interactions played a predominant role as the driving force for binding process of DPZ and GLM to hAChE. Moreover, the predicted total binding free energy of hAChE/DPZ was stronger than hAChE/GLM, which was consistent well with the experimental data. We hope that our findings provide useful information for further design of novel hAChE inhibitors.
HIGHLIGHTS
- Anti-Alzheimer’s drugs donepezil and galantamine in complex with human acetylcholinesterase were explored by MD simulations and binding free energy calculations
- The MM-PB(GB)SA-based binding free energy indicated that donepezil exhibited a more favorable binding affinity to human acetylcholinesterase than galantamine
- The molecular rotation of galantamine during MD simulation resulted in the reduction of hydrogen bond occupancies with D74 and S203
- The van der Waals interactions were considered as the major contributor to the binding of both drugs
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Alzheimer's Association. 2020 Alzheimer's disease facts and figures. Alzheimer's Dement. 2020; 16, 391-460.
MW Bondi, EC Edmonds and DP Salmon. Alzheimer's disease: Past, present, and future. J. Int. Neuropsychol. Soc. 2017; 23, 818-31.
M Giri, M Zhang and Y Lü. Genes associated with Alzheimer’s disease: An overview and current status. Clin. Interv. Aging. 2016; 11, 665-81.
JM Long and DM Holtzman. Alzheimer disease: An update on pathobiology and treatment strategies. Cell 2019; 179, 312-39.
MVF Silva, CMG Loures, LCV Alves, LC de Souza, KBG Borges and MG Carvalho. Alzheimer's disease: Risk factors and potentially protective measures. J. Biomed. Sci. 2019; 26, 33.
EE Congdon and EM Sigurdsson. Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 2018; 14, 399-415.
F Panza, M Lozupone, G Logroscino and BP Imbimbo. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 2019; 15, 73-88.
CM Henstridge, BT Hyman and TL Spires-Jones. Beyond the neuron - cellular interactions early in Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 2019; 20, 94-108.
TH Ferreira-Vieira, IM Guimaraes, FR Silva and FM Ribeiro. Alzheimer's disease: Targeting the cholinergic system. Curr. Neuropharmacol. 2016; 14, 101-15.
A Sanabria-Castro, I Alvarado-Echeverría and C Monge-Bonilla. Molecular pathogenesis of Alzheimer’s disease: An update. Ann. Neurosci. 2017; 24, 46-54.
K Sharma. Cholinesterase inhibitors as Alzheimer's therapeutics (Review). Mol. Med. Rep. 2019; 20, 1479-87.
R León, AG Garcia and J Marco-Contelles. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer's disease. Med. Res. Rev. 2013; 33, 139-89.
R Cacabelos. Donepezil in Alzheimer's disease: From conventional trials to pharmacogenetics. Neuropsychol. Dis. Treat. 2007; 3, 303-33.
DA Casey, D Antimisiaris and J O'Brien. Drugs for Alzheimer's disease: Are they effective? Pharma. Therapeut. 2010; 35, 208-11.
A Nordberg, T Darreh-Shori, E Peskind, H Soininen, M Mousavi, G Eagle and R Lane. Different cholinesterase inhibitor effects on CSF cholinesterases in Alzheimer patients. Curr. Alzheimer Res. 2009; 6, 4-14.
H Sugimoto, H Ogura, Y Arai, Y Iimura and Y Yamanishi. Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn. J. Pharmacol. 2002; 89, 7-20.
LJ Scott and KL Goa. Galantamine: A review of its use in Alzheimer's disease. Drugs 2000; 60, 1095-122.
MCR Simoes, FPD Viegas, MS Moreira, MDF Silva, MM Riquiel, PMD Rosa, MR Castelli, MHD Santos, MG Soares and C Viegas. Donepezil: An important prototype to the design of new drug candidates for Alzheimer's disease. Mini Rev. Med. Chem. 2014; 14, 2-19.
JL Sussman, M Harel, F Frolow, C Oefner, A Goldman, L Toker and I Silman. Atomic structure of acetylcholinesterase from Torpedo californica: A prototypic acetylcholine-binding protein. Science 1991; 253, 872-9.
H Dvir, I Silman, M Harel, TL Rosenberry and JL Sussman. Acetylcholinesterase: From 3D structure to function. Chem. Biol. Interact. 2010; 187, 10-22.
A Ordentlich, D Barak, C Kronman, N Ariel, Y Segall, B Velan and A Shafferman. Functional characteristics of the oxyanion hole in human acetylcholinesterase. J. Biol. Chem. 1998; 273, 19509-17.
TL Rosenberry, X Brazzolotto, IR MacDonald, M Wandhammer, M Trovaslet-Leroy, S Darvesh and F Nachon. Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase: A crystallographic, kinetic and calorimetric study. Molecules 2017; 22, 2098.
G Johnson and SW Moore. The peripheral anionic site of acetylcholinesterase: Structure, functions and potential role in rational drug design. Curr. Pharmaceut. Des. 2006; 12, 217-25.
J Cheung, MJ Rudolph, F Burshteyn, MS Cassidy, EN Gary, J Love, MC Franklin and JJ Height. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J. Med. Chem. 2012; 55, 10282-6.
ML Bolognesi, R Banzi, M Bartolini, A Cavalli, A Tarozzi, V Andrisano, A Minarini, M Rosini, V Tumiatti, C Bergamini, R Fato, G Lenaz, P Hrelia, A Cattaneo, M Recanatini and C Melchiorre. Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease. J. Med. Chem. 2007; 50, 4882-97.
R Salomon-Ferrer, DA Case and RC Walker. An overview of the Amber biomolecular simulation package. Wires Comput. Mol. Sci. 2013; 3, 198-210.
Y Duan, C Wu, S Chowdhury, MC Lee, G Xiong, W Zhang, R Yang, P Cieplak, R Luo, T Lee, J Caldwell, J Wang and P Kollman. A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J. Comput. Chem. 2003; 24, 1999-2012.
MHM Olsson, CR Søndergaard, M Rostkowski and JH Jensen. PROPKA3: Consistent treatment of internal and surface residues in empirical pKa predictions. J. Chem. Theor. Comput. 2011; 7, 525-37.
J Wiesner, Z Kříž, K Kuča, D Jun and J Koča. Acetylcholinesterases - the structural similarities and differences. J. Enzym. Inhib. Med. Chem. 2007; 22, 417-24.
WL Jorgensen, J Chandrasekhar, JD Madura, RW Impey and ML Klein. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983; 79, 926-35.
P Mahalapbutr, P Chusuth, N Kungwan, W Chavasiri, P Wolschann and T Rungrotmongkol. Molecular recognition of naphthoquinone-containing compounds against human DNA topoisomerase IIα ATPase domain: A molecular modeling study. J. Mol. Liq. 2017; 247, 374-85.
W Panman, B Nutho, S Chamni, S Dokmaisrijan, N Kungwan and T Rungrotmongkol. Computational screening of fatty acid synthase inhibitors against thioesterase domain. J. Biomol. Struct. Dynam. 2018; 36, 4114-25.
K Sanachai, P Mahalapbutr, K Choowongkomon, RP Poo-Arporn, P Wolschann and T Rungrotmongkol. Insights into the binding recognition and susceptibility of tofacitinib toward janus kinases. ACS Omega 2020; 5, 369-77.
MJ Frisch, GW Trucks, HB Schlegel, GE Scuseria, MA Robb, JR Cheeseman, G Scalmani, V Barone, B Mennucci, GA Petersson, H Nakatsuji, M Caricato, X Li, HP Hratchian, AF Izmaylov, J Bloino, G Zheng, JL Sonnenberg, M Hada, …, DJ Fox. Gaussian 09; Gaussian, Inc. Wallingford CT 2009; 32, 5648-52.
J Wang, W Wang, PA Kollman and DA Case. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. Model. 2006; 25, 247-60.
J Wang, RM Wolf, JW Caldwell, PA Kollman and DA Case. Development and testing of a general amber force field. J. Comput. Chem. 2004; 25, 1157-74.
DM York, TA Darden and LG Pedersen. The effect of long-range electrostatic interactions in simulations of macromolecular crystals: A comparison of the Ewald and truncated list methods. J. Chem. Phys. 1993; 99, 8345-8.
JP Ryckaert, G Ciccotti and HJC Berendsen. Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. J. Comput. Phys. 1977; 23, 327-41.
HJC Berendsen, JPM Postma, WF van Gunsteren, A DiNola and JR Haak. Molecular dynamics with coupling to an external bath. J. Comput. Phys. 1984; 81, 3684-90.
C Wang, D Greene, L Xiao, R Qi and R Luo. Recent developments and applications of the MMPBSA method. Front. Mol. Biosci. 2018; 4, 87.
E Wang, H Sun, J Wang, Z Wang, H Liu, JZH Zhang and T Hou. End-point binding free energy calculation with MM/PBSA and MM/GBSA: Strategies and applications in drug design. Chem. Rev. 2019; 119, 9478-508.
H Gohlke and DA Case. Converging free energy estimates: MM-PB(GB)SA studies on the protein - protein complex Ras - Raf. J. Comput. Chem. 2004; 25, 238-50.
F Tama and YH Sanejouand. Conformational change of proteins arising from normal mode calculations. Protein Eng. 2001; 14, 1-6.
G Kryger, I Silman and JL Sussman. Structure of acetylcholinesterase complexed with E2020 (Aricept®): Implications for the design of new anti-Alzheimer drugs. Structure 1999; 7, 297-307.
C Guillou, A Mary, DZ Renko, E Gras and C Thal. Potent acetylcholinesterase inhibitors: Design, synthesis and structure-activity relationships of alkylene linked bis-galanthamine and galanthamine-galanthaminium salts. Bioorg. Med. Chem. Lett. 2000; 10, 637-9.
W Innok, A Hiranrat, N Chana, T Rungrotmongkol and P Kongsune. In silico and in vitro anti-AChE activity investigations of constituents from Mytragyna speciosa for Alzheimer’s disease treatment. J. Comput. Aid. Mol. Des. 2021; 35, 325-36.
B Nutho, P Mahalapbutr, K Hengphasatporn, NC Pattaranggoon, N Simanon, Y Shigeta, S Hannongbua and T Rungrotmongkol. Why are lopinavir and ritonavir effective against the newly emerged coronavirus 2019? Atomistic insights into the inhibitory mechanisms. Biochemistry 2020; 59, 1769-79.
T Hou, J Wang, Y Li and W Wang. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics dimulations. J. Chem. Inform. Model. 2010; 51, 69-82.
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